VOLUME 30 䡠 NUMBER 13
JOURNAL OF CLINICAL ONCOLOGY
Jennifer J. Griggs, University of Michigan,
Ann Arbor, MI; Pamela B. Mangu, Ameri-
can Society of Clinical Oncology, Alexan-
dria, VA; Holly Anderson, Breast Cancer
Coalition of Rochester; Michelle Shayne,
University of Rochester Medical Center,
Rochester; Lara E. Sucheston, Roswell
Park Cancer Institute, Cancer Prevention
and Control, Buffalo, NY; Edward P.
Balaban, University of Pittsburgh Cancer
Centers Network, Pittsburgh, PA; James J.
Dignam, University of Chicago, Chicago, IL;
William M. Hryniuk, CarePath, Toronto,
Ontario, Canada; Vicki A. Morrison, Univer-
sity of Minnesota Veterans Affairs Medical
Center, Minneapolis, MN; T. May Pini,
Medical Oncology, Houston, TX; Carolyn D.
Runowicz, Florida International University,
Miami, FL; Gary L. Rosner, Johns Hopkins
University, Baltimore, MD; Alex Sparre-
boom, St Jude Children’s Research Hospi-
tal, Memphis, TN; and Gary H. Lyman,
Duke University and the Duke Cancer Insti-
tute, Durham, NC.
Submitted October 7, 2011; accepted
February 21, 2012; published online
ahead of print at www.jco.org on April
2, 2012.
American Society of Clinical Oncology Clini-
cal Practice Guideline Committee
Approved: November 9, 2011.
Editor’s note: This represents a brief
summary overview of the complete new
American Society of Clinical Oncology
(ASCO) Clinical Practice Guideline on
Appropriate Chemotherapy Dosing for
Obese Adult Patients With Cancer and
provides recommendations with brief
discussions of the relevant literature for
each. The complete guideline, which
includes comprehensive discussions of the
literature, methodology information, and all
cited references, and Data Supplements
with the evidence tables the Panel used to
formulate these recommendations, are
available at www.asco.org/guidelines/wbd.
Authors’ disclosures of potential conflicts
of interest and author contributions are
found at the end of this article.
Corresponding author: American Society of
Clinical Oncology, 2318 Mill Rd, Suite 800,
Alexandria, VA 22314; e-mail: guidelines@
asco.org.
© 2012 by American Society of Clinical
Oncology
0732-183X/12/3013-1553/$20.00
DOI: 10.1200/JCO.2011.39.9436
Information downloaded from jco.ascopubs.org and provided by at CARILION ROANOKE MEM HOSP on May 2, 2012 from
Copyright © 2012 American Society of Clinical Oncology. All rights reserved.
䡠 MAY 1 2012
A S C O S P E C I A L A R T I C L E
Appropriate Chemotherapy Dosing for Obese Adult
Patients With Cancer: American Society of Clinical
Oncology Clinical Practice Guideline
Jennifer J. Griggs, Pamela B. Mangu, Holly Anderson, Edward P. Balaban, James J. Dignam,
William M. Hryniuk, Vicki A. Morrison, T. May Pini, Carolyn D. Runowicz, Gary L. Rosner,
Michelle Shayne, Alex Sparreboom, Lara E. Sucheston, and Gary H. Lyman
See related articles in J Oncol Pract doi: 10.1200/JOP.2012.000623 and doi: 10.1200/
JOP.2012.000606
A B S T R A C T
Purpose
To provide recommendations for appropriate cytotoxic chemotherapy dosing for obese adult
patients with cancer.
Methods
The American Society of Clinical Oncology convened a Panel of experts in medical and gynecologic
oncology, clinical pharmacology, pharmacokinetics and pharmacogenetics, and biostatistics and a
patient representative. MEDLINE searches identified studies published in English between 1996
and 2010, and a systematic review of the literature was conducted. A majority of studies involved
breast, ovarian, colon, and lung cancers. This guideline does not address dosing for novel targeted
agents.
Results
Practice pattern studies demonstrate that up to 40% of obese patients receive limited chemo-
therapy doses that are not based on actual body weight. Concerns about toxicity or overdosing in
obese patients with cancer, based on the use of actual body weight, are unfounded.
Recommendations
The Panel recommends that full weight–based cytotoxic chemotherapy doses be used to treat obese
patients with cancer, particularly when the goal of treatment is cure. There is no evidence that short- or
long-term toxicity is increased among obese patients receiving full weight–based doses. Most data indicate
that myelosuppression is the same or less pronounced among the obese than the non-obese who are
administered full weight– based doses. Clinicians should respond to all treatment-related toxicities in
obese patients in the same ways they do for non-obese patients. The use of fixed-dose chemotherapy
is rarely justified, but the Panel does recommend fixed dosing for a few select agents. The Panel
recommends further research into the role of pharmacokinetics and pharmacogenetics to guide
appropriate dosing of obese patients with cancer.
J Clin Oncol 30:1553-1561. © 2012 by American Society of Clinical Oncology
chemotherapy should be considered an indicator
INTRODUCTION
of quality of care.3,8,9 Despite studies confirming
Optimal doses of chemotherapy drugs or drug the safety and importance of full weight– based
combinations are generally established through cytotoxic (intravenous [IV] and oral) chemother-
randomized controlled clinical trials (RCTs). In apy dosing, many overweight and obese patients
adult patients with cancer, drug dosing has tradi- continue to receive limited chemotherapy doses.10-13
tionally been based on a patient’s estimated body Practice pattern studies demonstrate that up to 40% of
surface area (BSA).1 There exists compelling evi- obese patients receive limited doses that are not based
dence that reductions from standard dose and on actual body weight.10,12-17 Many oncologists con-
dose-intensity may compromise disease-free sur- tinue to use either ideal body weight or adjusted ideal
vival (DFS) and overall survival (OS) in the cura- body weight or to cap the BSA at, for example, 2.0 m2
tive setting.2-7 Furthermore, a number of authors rather than use actual body weight to calculate BSA.
have suggested that the optimal delivery of cancer Moreover, considerable variation in the dosing of
© 2012 by American Society of Clinical Oncology 1553
186.124.42.244
 Griggs et al
chemotherapy in overweight and obese individuals with cancer has
been documented,3,13,14,16,18-22 suggesting considerable uncertainty
among physicians about optimal dose selection.
The practice of limiting doses in overweight and obese pa-
tients may negatively influence the quality of care and outcomes at
a population level, given the rise in rates of obesity both in the
United States23,24 and globally.25 Rates of obesity have increased in
recent years, reaching epidemic proportions in the United States.
THE BOTTOM LINE
ASCO GUIDELINE
ASCO Guideline on Appropriate Chemotherapy
Dosing for Obese Adult Patients With Cancer
Intervention
● Recommendations for appropriate chemotherapy dosing
for obese adult patients with cancer
Target Audience
● Medical oncologists, pharmacists, oncology nurses
Key Recommendations
● Panel recommends that full weight– based chemotherapy
doses be used in the treatment of the obese patient with
cancer, particularly when the goal of treatment is cure.
● Clinicians should respond to all treatment-related toxicities
in obese patients with cancer in the same ways they do for
non-obese patients.
● If a dose reduction is employed in response to toxicity, con-
sideration should be given to the resumption of full weight–
based doses for subsequent cycles, especially if a possible
cause of toxicity (eg, impaired renal, hepatic function) has
been resolved; there is no evidence to support the need for
greater dose reductions for obese patients compared with
non-obese patients.
● The use of fixed-dose cytotoxic chemotherapy is rarely justi-
fied (except for a few select agents).
Methods
● Systematic review of the medical literature and analysis of
the medical literature by the Update Committee of an Ex-
pert Panel
Additional Information
● Recommendations and a brief summary of the literature
and analysis are provided in this Executive Summary
The full guideline with methodology, comprehensive discussions
of the literature, full reference list, Data Supplements, evidence
tables, and clinical tool and resources can be found at www.
asco.org/guidelines/wbd. Patient information is available at
www.cancer.net.
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186.124.42.244
The Centers for Disease Control and Prevention estimates that a
majority (⬎ 60%) of adult Americans have a body mass index
(BMI) ⬎ 25 (overweight, obese, morbidly obese) and that this pro-
portion is steadily increasing.23,24 Poorer outcomes among obese pa-
tients are most likely multifactorial.26 Systemic chemotherapy at
less than full weight– based dosing and unnecessary dose reduc-
tions may explain, in part, the significantly higher cancer mortality
rates observed in overweight and obese individuals. Concerns
about overdosing in the obese cancer patient based on the use of
actual body weight are unfounded.10,13,19,27-29 A compelling body
of evidence exists supporting the important relationship between
selection of appropriate chemotherapy doses in adult patients with
cancer and treatment efficacy and toxicity as well as pharmacoki-
netic correlates of dose selection.2,5,6,10,13,18,27-90
METHODS
Panel Composition
An Expert Panel met once in person and considered data from a system-
atic review and interacted through e-mail throughout draft development. The
Panel authored recommendations for clinicians who treat obese patients with
cancer with cytotoxic chemotherapy (IV and oral agents). The Panel members
are listed in Appendix Table A1 (online only).
Literature Review and Analysis
Literature search strategy. The MEDLINE and the Cochrane Collabora-
tion Library electronic databases were searched with the date parameters of
1966 through October 2010 for articles in English. MEDLINE search terms are
included in Data Supplement 3, and a summary of the literature search results
is provided in Data Supplement 4 at www.asco.org/guidelines/wbd.
Inclusion and exclusion criteria. Articles were selected for inclusion in
the systematic review if they were published English language studies on
cytotoxic IV or oral chemotherapy dosing approaches for overweight or obese
patients with cancer, excluding leukemias. Data were extracted from prospec-
tive or retrospective cohort studies that addressed withholding, delaying, early
cessation, or reduction of chemotherapy doses, including capping doses (eg, at
a BSA of 2.0 m2). Data were also extracted about treatment toxicity, DFS and
OS, and quality-of-life outcomes. Systematic reviews of RCTs, meta-analyses,
and other clinical practice guidelines were also conducted. Because of the
paucity of data, this guideline does not address dosing for novel targeted agents
such as tyrosine kinase inhibitors, immunotherapies (eg, interleukin-2, inter-
feron), or monoclonal antibodies. Pharmacokinetic studies with pharmaco-
dynamic or clinical outcomes with appropriate controls were also included.
Data extraction. Primary outcome measures of interest included OS,
disease-specific survival, DFS, relapse-free survival, event-free survival,
progression-free survival (PFS), and treatment-related toxicities. Second-
ary outcomes and/or other data elements of interest included quality of life
and costs of care.
Study Quality and Limitations of the Literature
There are no prospective randomized studies comparing full weight–
based chemotherapy dose selection and non–full weight– based dose selection.
Retrospective analyses of randomized trials and comparative observational
studies comprise the majority of the studies included in this guideline. This
guideline is based on evidence derived primarily from subgroup analyses and
registry data. Although the results are important, it should be clear to the
reader that the evidence base for this guideline is necessarily different from
those for other American Society of Clinical Oncology (ASCO) guidelines.
Definition of Terms
A glossary of terms, including information on calculating BSA (eg,
Mosteller, Dubois and Dubois, Haycock, Gehan and George, Boyd formu-
las) and toxicity grades, appears in Data Supplement 5 at www.asco.org/
guidelines/wbd.
JOURNAL OF CLINICAL ONCOLOGY
 ASCO Guideline on Weight-Based Dosing
Guideline Policy
This Executive Summary for clinicians is an abridged summary of an
ASCO clinical practice guideline. The guideline and this summary are not
intended to substitute for the independent professional judgment of the treat-
ing physician. Practice guidelines do not account for individual variation
among patients and may not reflect the most recent evidence. This summary
does not recommend any particular product or course of medical treatment.
Use of the practice guideline and this summary is voluntary. The full practice
guideline and additional information are available at http://www.asco.org/
guidelines/wbd.
Guideline and Conflicts of Interest
The Expert Panel was assembled in accordance with the ASCO Conflict
of Interest Management Procedures for Clinical Practice Guidelines (summa-
rized at http://www.asco.org/guidelinescoi). Members of the Panel completed
the ASCO disclosure form, which requires disclosure of financial and other
interests that are relevant to the subject matter of the guideline, including
relationships with commercial entities that are reasonably likely to experience
direct regulatory or commercial impact as a result of promulgation of the
guideline. Categories for disclosure include employment relationships, con-
sulting arrangements, stock ownership, honoraria, research funding, and ex-
pert testimony. In accordance with the Procedures, the majority of the
members of the Panel did not disclose any of these relationships.
RESULTS
The overarching question for this clinical practice guideline is:
Should actual body weight be used to select chemotherapy doses in
obese individuals with cancer? For adults, overweight and obesity
ranges are determined by using weight and height to calculate BMI.
For more information about interpreting BMI, visit the Centers for
Disease Control and Prevention Web site.91 An adult who has a BMI
between 25 and 29.9 kg/m2 is considered overweight; an adult who has a
BMI of ⱖ 30 kg/m2 is considered obese; an adult who has a BMI ⬎ 40
kg/m2 (or⬎35kg/m2 withcomorbidconditions)isconsideredmorbidly
obese. More information about interpreting BMI for adults is pro-
vided in Data Supplement 6 at www.asco.org/guidelines/wbd. Table 1
provides a summary of the following guideline recommendations.
GUIDELINE RECOMMENDATIONS
Clinical Question 1
Is there evidence that full weight– based dosing increases toxicity
in obese patients with cancer?
Recommendation 1.1. The Panel recommends that actual body
weight be used when selecting cytotoxic chemotherapy doses regard-
less of obesity status. There is no evidence that short- or long-term
toxicity is increased among obese patients receiving full weight– based
chemotherapy doses. Most data indicate that myelosuppression is the
same or less pronounced among the obese than the non-obese when
administered full weight– based doses.
Literature review and analysis. Observational studies and retro-
spective analyses of participants in clinical trials have not demon-
strated increased hematologic or nonhematologic toxicity in obese
patients receiving chemotherapy doses calculated using actual body
weight. For example, no excess toxicity was observed among patients
with small-cell lung cancer when actual weight was used to calculate
chemotherapy doses.28 In a retrospective analysis of CALGB (Cancer
and Leukemia Group B) Protocol 8541, obese patients receiving full
weight– based dosing of adjuvant cyclophosphamide, doxorubicin,
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186.124.42.244
and fluorouracil had no excess grade 3 hematologic or nonhemato-
logic toxicity at any of the three dose levels in the study compared with
non-obese patients.27 In obese patients receiving full weight– based
doses of cyclophosphamide, methotrexate, and fluorouracil in the
adjuvant treatment of breast cancer, patients with the highest BMIs
had the highest leukocyte nadir values, or leukocyte nadirs were less
pronounced among obese patients compared with non-obese pa-
tients.29 A large study of 9,672 patients with breast cancer treated in
practices across the United States with adjuvant doxorubicin and
cyclophosphamide demonstrated that the likelihood of febrile neutro-
penia, if anything, decreased as BMI increased among those patients
who received full weight– based dosing.13 Similar findings were re-
ported in the treatment of 59 women with endometrial or ovarian
cancer and BSA ⬎ 2.0 m2 who received paclitaxel and carboplatin
based on actual body weight.92 On the basis of these studies and others
included in the systematic review,93-96 the Panel concluded that there
is no evidence indicating higher rates of hematologic or nonhemato-
logic toxicity among obese patients who received full weight– based
doses. The heavier a patient is, even fully dosed, the less likely he or she
is to experience febrile neutropenia, especially in the absence of addi-
tional comorbid illness.
Recommendation 1.2. The Panel recommends full weight–
based chemotherapy dosing for morbidly obese patients with cancer,
subject to appropriate consideration of other comorbid conditions.
Data are extremely limited regarding optimal dose selection among
the morbidly obese and other special subgroups. More studies are
needed to evaluate optimal agents and agent combinations for obese
and morbidly obese patients with cancer; however, on the basis of
available information, it seems likely that the same principles regard-
ing dose selection for obese patients apply to the morbidly obese.
Literature review and analysis. Nine articles were found in a sepa-
rate search for morbidly obese patients with cancer97-105; these were small
observational studies or case reports and primarily presented data on the
pharmacokinetics of chemotherapy in this subgroup. For this reason,
there are no separate recommendations for morbidly obese patients in
this guideline. From the available evidence, it seems that morbidly
obese patients being treated with curative intent and receiving full
weight– based doses were no more likely to experience toxicity than
lean patients.106 Clinicians need to calculate full weight– based dosing
and use clinical judgment when monitoring toxicity, as they would for
all patients.107 The Panel recognizes that there may be cases in which
obese patients have other serious medical problems, and it encourages
clinicians to use judgment when dosing, as they would if the patients
were not obese (eg, heart, renal, pulmonary problems).
Clinical Question 2
Is there evidence that less than full weight– based dosing compro-
mises efficacy in obese patients with cancer?
Recommendation 2.1. The Panel recommends that full weight–
based chemotherapy doses (IV and oral) be used in the treatment of
the obese patient with cancer, particularly when the goal of treatment
is cure. Selecting reduced doses in this setting may result in poorer DFS
and OS rates. There are compelling data in patients with breast cancer
that reduced dose-intensity chemotherapy is associated with increased
disease recurrence and mortality. Although data in other malignancies
are more limited, based on improved survival observed with chemo-
therapy compared with controls, a dose-response relationship exists
for many responsive malignancies. Therefore, although data are not
© 2012 by American Society of Clinical Oncology 1555
 Griggs et al

Table 1. Clinical Questions and Recommendations

Clinical Question
1. Is there evidence that full weight–based
dosing increases toxicity in obese patients
with cancer?
2. Is there evidence that less than full
weight–based dosing compromises
efficacy in obese patients with cancer?
3. If an obese patient experiences high-
grade toxicity, should chemotherapy
doses or schedules be modified
differently from modifications used for
non-obese patients with cancer?
4. Is the use of fixed-dose (dose prescribed Recommendation 4.1: The Panel recommends consideration of fixed dosing only with select cytotoxic agents
independently of weight or BSA) cytotoxic
chemotherapy ever justified? Are there
unique dosing considerations for certain
chemotherapeutic agents?
5. How should BSA be calculated?
Specifically, what is the best formula for
use with the obese patient with cancer?
6. What is the role of pharmacokinetic and/ Recommendation 6.1: The Panel recommends further research into the role of pharmacokinetic and
or phamacogenetic factors when
determining optimal chemotherapy dose
and delivery (bolus, infusional, therapeutic
drug monitoring) for obese patients
with cancer?
Recommendation
Recommendation 1.1: The Panel recommends that actual body weight be used when selecting cytotoxic chemo-
therapy doses regardless of obesity status. There is no evidence that short- or long-term toxicity is increased
among obese patients receiving full weight–based chemotherapy doses. Most data indicate that
myelosuppression is the same or less pronounced among the obese than the non-obese administered full
weight–based doses.
Recommendation 1.2: The Panel recommends full weight–based chemotherapy dosing for morbidly obese
patients with cancer, subject to appropriate consideration of other comorbid conditions. Data are extremely
limited regarding optimal dose selection among the morbidly obese and other special subgroups. More
studies are needed to evaluate optimal agents and agent combinations for obese and morbidly obese patients
with cancer; however, based on available information, it seems likely that the same principles regarding dose
selection for obese patients apply to the morbidly obese.
Recommendation 2.1: The Panel recommends that full weight–based chemotherapy doses (IV and oral) be used
in the treatment of the obese patient with cancer, particularly when the goal of treatment is cure. Selecting
reduced doses in this setting may result in poorer disease-free and overall survival rates. There are compelling
data in patients with breast cancer that reduced dose-intensity chemotherapy is associated with increased
disease recurrence and mortality. Although data in other malignancies are more limited, based on improved
survival observed with chemotherapy compared with controls, a dose-response relationship exists for many
responsive malignancies. Therefore, although data are not available to address this question for all cancer
types, in the absence of data demonstrating sustained efficacy for reduced dose chemotherapy, the Panel
believes that the prudent approach is to provide full weight–based chemotherapy dosing to obese patients
with cancer, especially those receiving treatment with curative intent. Most of the data in support of full
weight–based dosing come from the treatment of early-stage disease. Data supporting the use of full weight–
based doses in the advanced disease setting are limited.
Recommendation 3.1: Clinicians should follow the same guidelines for dose reduction, regardless of obesity
status, for all patients, depending on the type and severity of toxicity, any comorbid conditions, and whether
the treatment intention is cure or palliation. There is no evidence to support the need for greater dose
reductions for obese patients compared with non-obese patients. If a dose reduction is employed in response
to toxicity, consideration should be given to the resumption of full weight–based doses for subsequent
cycles, especially if a possible cause of toxicity (eg, impaired renal, hepatic function) has been resolved. The
Panel recognizes the need for clinicians to exercise judgment when providing care for patients who have
experienced grade 3 or 4 chemotherapy toxicity. The presence of obesity alone should not alter such
clinical judgment.
(eg, carboplatin and bleomycin). On the basis primarily of neurotoxicity concerns, vincristine is capped at a
maximum dose of 2.0 mg when used as part of the CHOP and CVP regimens. Several other cytotoxic chemo-
therapeutic agents have been used in clinical trials at a fixed dose independent of patient weight or BSA.
However, it is not clear that fixed dosing is optimal for any of these other agents.
Recommendation 5.1: The Panel recommends that BSA be calculated using any of the standard formulae. There
is no evidence to support one formula for calculating BSA over another.
pharmacogenetic information for guiding the dosing of IV and oral chemotherapeutic agents for adult patients
with cancer who are obese. It should be emphasized that there is a paucity of information on the influence of
obesity on the pharmacokinetics of most anticancer drugs from properly powered trials. This is the result, in
part, of empiric eligibility restrictions from the outset in clinical trials and a lack of pharmacokinetic analyses
performed and published for this subpopulation. Overall, there are insufficient pharmacokinetic data to reject
the recommendation to use a full weight–based dosing strategy for chemotherapeutic agents in patients with
cancer who are obese, regardless of route of administration and/or infusion time.

Abbreviations: BSA, body surface area; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CVP, cyclophosphamide, vincristine, prednisone; IV, intravenous.

available to address this question for all cancer types, in the absence of
data demonstrating sustained efficacy for reduced-dose chemothera-
py, the Panel believes that the prudent approach is to provide full
weight– based chemotherapy dosing to obese patients with cancer,
especially those receiving treatment with curative intent. Most of the
data in support of full weight– based dosing come from the treatment
of early-stage disease. Data supporting the use of full weight– based
doses in the advanced disease setting are limited.
Literature review and analysis. Retrospective analyses and obser-
vational studies suggest that dose limits in obese patients may com-
promise DFS and OS rates.108-111 An analysis of outcomes among
obese patients treated in CALGB 8541 demonstrated that obese pa-
tients who received ⬍ 95% of the expected chemotherapy (based on
full weight– based dosing) had worse failure-free survival rates.27 Ad-
ditional data supporting the use of full weight– based dosing came
from a retrospective analysis of four adjuvant chemotherapy studies
conducted by the International Breast Cancer Study Group (previ-
ously the Ludwig Study Group). In this analysis, obese patients with
estrogen receptor–negative breast cancer who received ⬍ 85% of the
dose experienced a higher relapse rate and had a lower survival rate.45
Clinical Question 3
If an obese patient experiences high-grade toxicity, should chem-
otherapy doses or schedules be modified differently from modifica-
tions used for non-obese patients with cancer?
Recommendation 3.1. Clinicians should follow the same guide-
lines for dose reduction, regardless of obesity status, for all patients,
depending on the type and severity of toxicity, any comorbid condi-
tions, and whether the treatment intention is cure or palliation. There
is no evidence to support the need for greater dose reductions for
obese patients compared with non-obese patients. If a dose reduction
is employed in response to toxicity, consideration should be given to

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186.124.42.244
 ASCO Guideline on Weight-Based Dosing
the resumption of full weight– based doses for subsequent cycles,
especially if a possible cause of toxicity (eg, impaired renal, hepatic
function) has been resolved. The Panel recognizes the need for clini-
cians to exercise judgment when providing care for patients who have
experienced grade 3 or 4 chemotherapy toxicity. The presence of
obesity alone should not alter such clinical judgment.
Literature review and analysis. There are no RCTs that specify
differential management of moderate to severe toxicity (grades 3 to 4)
according to obesity status (Data Supplement 5 at www.asco.org/
guidelines/wbd provides more information on toxicity grades). Simi-
larly, no observational studies describe BMI-based management of
toxicities from chemotherapy. Given the lack of evidence citing harms
in differential treatment, the Panel recommends clinicians respond to
treatment-related toxicities in obese patients with cancer in the same
ways they do for non-obese patients with cancer. Excess toxicity usu-
ally results from the fact that the patient has reduced drug elimination
in reference to the dose of one (or more) chemotherapeutic agent. A
return to initial dosing after toxicity is resolved rarely occurs unless the
reason for toxicity is clearly established and fully resolved. Thus, the
dose should only be increased to the initial dose if it is established that
drug elimination has improved (eg, improvement in renal function,
return of bilirubin to normal, significant improvement in perfor-
mance status). Obesity status alone should not play a role in dose
modifications in response to toxicity.
Clinical Question 4
Is a fixed dose (dose prescribed independently of weight or BSA)
of cytotoxic chemotherapy ever justified? Are there unique dosing
considerations for certain chemotherapeutic agents?
Recommendation 4.1. The Panel recommends consideration of
fixed dosing only with select cytotoxic agents (eg, carboplatin and
bleomycin). On the basis primarily of neurotoxicity concerns, vincris-
tine is capped at a maximum dose of 2.0 mg when used as part of the
CHOP (cyclophosphamide, hydroxydoxorubicin [doxorubicin], vin-
cristine, prednisone) and CVP (cyclophosphamide, vincristine, pred-
nisone) regimens. Several other cytotoxic chemotherapeutic agents
have been used in clinical trials at a fixed dose independent of patient
weight or BSA. However, it is not clear that fixed dosing is optimal for
any of these other agents.
Literature review and analysis. The Panel recommends consid-
eration of fixed dosing only with a select group of agents. For example,
carboplatin clearance depends on glomerular filtration rate (GFR),
and doses are calculated best using the Calvert formula112,113 (total
dose [mg] ⫽ [AUC (target area under the plasma concentration-time
curve)] ⫻ [GFR ⫹ 25]) to achieve a targeted AUC. The GFR used in
the Calvert formula to calculate AUC dosing should not exceed 125
mL/min. The maximum carboplatin dose should not exceed AUC
(mg ⫻ min/mL) ⫻ 150 mL/min. Because carboplatin clearance is
dictated by renal filtration, and GFR correlates with BSA, dosing of
carboplatin in the obese patient with cancer based on GFR may be
most reasonable. There are several agents that are sometimes pre-
scribed at a fixed dose or capped based on the dose that was used in
clinical trials. The usual adult dose of bleomycin for testicular cancer is
a fixed dose in a BEP (bleomycin, etoposide, cisplatin) regimen.114 In
R-CHOP (rituximab plus CHOP), CHOP, and CVP regimens, the
dose of vincristine is capped at a maximum of 2 mg.115,116
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Of note, the use of flat-fixed dosing of irinotecan has been previ-
ously examined but not in large clinical trials.39,117 In general onco-
logic practice, dosing for irinotecan remains based on BSA.
There are other agents that have been used in fixed doses in
non-RCTs of the treatment of specific cancers in unique patient
populations; these include agents such as metronomic cyclophos-
phamide118-123 and capecitabine.124 Fixed dosing based on BMI or
BSA categories is possible and has been proposed for some agents
(eg, cisplatin), but such approaches have never been prospec-
tively evaluated.100
Clinical Question 5
How should BSA be calculated? Specifically, what is the best
formula for use in the obese patient with cancer?
Recommendation 5.1. The Panel recommends that BSA be cal-
culated using any of the standard formulas (eg, Mosteller, DuBois and
Dubois, Haycock, Gehan and George, Boyd formulas). There is no
evidence to support one formula for calculating BSA over another.
Literature review and analysis. Formulas for calculating BSA
were not developed for use in the obese or morbidly obese and/or
those with multiple comorbid conditions and do not take into
account patient sex. In fact, there may be noticeable differences
(⬎ 10%) in calculated values of BSA, especially at the extremes of
weight and/or height, resulting in noticeable differences in dosing.
There are ongoing efforts to establish a new BSA equation suitable for
a typical 21st century population, because ⬎ 60% of adult Americans
have BMIs ⬎ 25 kg/m2, and this proportion is steadily increasing.23,24
Data Supplement 5 at www.asco.org/guidelines/wbd includes BSA
formulas currently used.
Clinical Question 6
What is the role of pharmacokinetic and/or pharmacogenetic
factors when determining optimal chemotherapy dose and delivery
(bolus, infusional, therapeutic drug monitoring) for obese patients
with cancer?
Recommendation 6.1. The Panel recommends further research
into the role of pharmacokinetic and pharmacogenetic information
for guiding the dosing of IV and oral chemotherapeutic agents for
adult patients with cancer who are obese. It should be emphasized that
there is a paucity of information on the influence of obesity on the
pharmacokinetics of most anticancer drugs from properly powered
trials. This is the result, in part, of empiric eligibility restrictions from
the outset in clinical trials and a lack of pharmacokinetic analyses
performed and published for this subpopulation. Overall, there are
insufficient pharmacokinetic data to reject the recommendation to
use a full weight– based dosing strategy for chemotherapeutic agents
in patients with cancer who are obese, regardless of route of adminis-
tration and/or infusion time.
Literature review and analysis. Clearance is the most important
pharmacokinetic parameter to consider when devising a dosing regi-
men for anticancer agents, because it is inversely related to the AUC.
This parameter has clinical relevance because it correlates with clinical
outcomes, although there are only a few examples in which the asso-
ciation is reproducible.125 For the majority of anticancer drugs, the
liver is the principal organ mediating clearance. The accumulation of
fat in the liver of obese patients may alter hepatic blood flow, and this
pathologic change might have an impact on clearance.102,126,127 The
© 2012 by American Society of Clinical Oncology 1557
 Griggs et al
other primary organs involved in the clearance of drugs are the kid-
neys. The processes involved in drug elimination through the kidneys
include glomerular filtration, tubular secretion, and tubular reabsorp-
tion. The effect of obesity on these functions is not entirely clear.127
The pharmacokinetics of some but not all drugs may be altered in
obese patients, but there is no single valid method to relate drug clearance
to degree of obesity, so changes in drug dosing are not currently recom-
mended. Three observations regarding drug clearance and obesity were
recently described128: (1) obese individuals exhibit higher absolute
drug clearance than do their non-obese counterparts; (2) clearance
does not increase linearly with total body weight; and (3) clearance and
lean body weight are correlated.
There is a general paucity of information from sufficiently
powered clinical studies on the influence of obesity on the phar-
macokinetics of most anticancer drugs. This is the result, in part, of
empiric eligibility restrictions from the outset in clinical trials
and a lack of pharmacokinetic analyses performed and published
for this subpopulation. In many studies, the obese patient may
be underrepresented.
Overall, there are insufficient pharmacokinetic data to reject the
Panel’s recommendation to use a full weight– based dosing strategy
for chemotherapeutic agents in patients with cancer who are obese,
regardless of route of administration and/or infusion time. To date,
there are no published pharmacogenetic articles meeting the inclusion
and exclusion criteria for this guideline that could have been included
in the discussion. Nevertheless, there may be a future role for applying
pharmacokinetic and pharmacogenetic principles in cancer chemo-
therapy dosing to achieve a more personalized approach to treatment
for the obese,129 although large prospective studies are certainly re-
quired to support this practice. For more information on the pharma-
cokinetic clearance of some chemotherapeutic agents (eg, cisplatin,
paclitaxel, troxacitabine, carboplatin, docetaxel, doxorubicin, irinote-
can, topotecan, and busulfan) and pharmacogenetics, refer to the full
guideline at www.asco.org/guidelines/wbd.
PATIENT AND CLINICIAN COMMUNICATION
Chemotherapy dose selection generally lies within the purview of the
treating physician. If obese patients or caregivers inquire about dosing,
however, a discussion of the evidence contained within this guideline
is appropriate. Physicians may have to explain to obese patients and
caregivers that higher doses are needed to be effective. In fact, subop-
timal treatment could result if dosing is not full weight based. It is
important to reassure patients that toxicity from the appropriate dose
of chemotherapy is not expected to be greater. Adverse effects will be
monitored closely. Patients should be warned that costs, even insur-
ance copays, may be higher.
Communication with other health care providers is also war-
ranted. Pharmacists and nursing professionals who are accus-
tomed to limiting chemotherapy doses for obese patients should be
informed of the existing evidence. IV and oral doses may be pre-
packaged for patients of normal weight, but appropriate dosing
should be delivered regardless of doses contained within a given
vial. Arbitrary capping based on drug procurement costs is unac-
ceptable (eg, one v 1.5 vials).
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Copyright © 2012 American Society of Clinical Oncology. All rights reserved.
186.124.42.244
HEALTH DISPARITIES
Some racial and ethnic minorities and patients of lower socioeco-
nomic status (SES) are at risk of suboptimal cancer care. Members
of some racial and ethnic minority groups and patients with fewer
financial resources tend to have a higher burden of comorbid
illness, are more likely to be uninsured or underinsured, and face
greater challenges in accessing high-quality health care.130-132
Awareness of disparities in quality of chemotherapy dose selection
should be considered in context.
Black/African American patients and patients of lower SES are
more likely to receive reduced doses of adjuvant chemotherapy in
the treatment of breast cancer.19,133 The higher rates of obesity
among blacks/African Americans, Hispanics/Latinos, and people
of lower SES134-136 only increase the likelihood of chemotherapy
dose limits among these patients, who already experience higher
case-fatality rates.137 Up to 40% of obese patients with breast
cancer receive substantially reduced chemotherapy doses (⬎ 10%
to 15% dose reduction), compared with doses that would be ad-
ministered if actual body weight were used in dose calcula-
tions.13,45 Given the systematic differences in chemotherapy dose
selection, it may be that black/African American women and
women of lower SES will reap the greatest benefits from a change in
the common practice of dose limitations in obese patients to full
weight– based dosing. It is reassuring that there is no evidence that
toxicity is more likely to occur when full weight– based doses
are used.13,27,106,138,139
LIMITATIONS OF THE RESEARCH AND FUTURE DIRECTIONS
The most obvious limitation of the evidence provided in support of
this guideline is the limited number of prospective RCTs directly
addressing the issue of weight-based dosing. Nonetheless, in addi-
tion to RCTs supporting the small but significant incremental
benefit of dose-intensified therapy compared with standard dose-
intensity, several trials have demonstrated a substantial reduction
in treatment efficacy, with reductions in relative dose-intensity below
standard doses and schedules. RCTs also have several well-recognized
limitations. Relevant RCTs are only available for the most common
malignancies (eg, breast, lung, and gynecologic cancers). Studying the
impact of relatively small reductions in dose-intensity would require a
large sample size to have sufficient power to assess the impact on
long-term outcomes such as OS. RCTs often use strict and limiting
eligibility criteria, excluding patients with comorbidities com-
monly encountered in those with cancer, which may reduce effec-
tiveness or increase toxicity but which often disqualify the patients
from the trial. Therefore, RCTs may not adequately address effec-
tiveness in the broader, unselected cancer population with major
medical comorbidities and treatment safety issues that may not
emerge until years later.
Given the data that do exist, many consider deliberate random
assignment of patients with responsive and potentially curable malig-
nancies to lower and potentially less effective dose-intensity to be
unethical. However, a rigorous systematic review of data from a series
of patients enrolled onto Cooperative Group trials— examining data
on all patients (with and without comorbid conditions) who are
JOURNAL OF CLINICAL ONCOLOGY
 ASCO Guideline on Weight-Based Dosing

defined as obese— could shed light on the issue of outcomes for obese obese patients and missing and/or inaccurately recorded clinical
patients with cancer. data affect prognosis and response to treatment.
Therefore, for both economic and ethical reasons, it is unlikely
that additional data from RCTs directly addressing this issue will
become available. Fortunately, there are abundant and compelling ADDITIONAL RESOURCES
supportive data from both prospective cohort studies and well-
done retrospective analyses of RCTs, which have almost univer- Data Supplements, including evidence tables, and clinical tools and
sally supported the clinical importance of maintaining relative resources can be found at www.asco.org/guidelines/wbd. Patient in-
dose-intensity in patients with cancer with responsive and poten- formation is available at www.cancer.net.
tially curable malignancies. Consistent pharmacokinetic and phar-
macodynamic studies all provide a firm underlying basis for the
recommendations provided in this guideline. It is essential that the AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
study hypothesis, study population, controls, measurements, ana-
lytic methods, and any subgroup analyses be defined a priori.
The author(s) indicated no potential conflicts of interest.
Well-designed prospective studies with planned analysis of body
composition and adverse events would be valuable. There is a real
need for data on both toxicity and efficacy in special populations AUTHOR CONTRIBUTIONS
such as the obese. As new drugs are being developed, it is important
for industry to at least provide pharmacokinetic and pharmacody- Administrative support: Pamela B. Mangu
namic data in real-world subgroups that may have been excluded Manuscript writing: All authors
from clinical trials. It is clear that clinician dosing decisions for Final approval of manuscript: All authors

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